This invention relates to methods for prevention and treatment of animal vital infections and, more particularly, to methods of prevention and treatment of human, animal and plant viral infections by inhibiting viral DNA and RNA synthesis.
It is well established that all viruses can be divided into two main groups according to the nature of the nucleic acid, DNA or RNA, which they possess. Both types of viruses are infectious disease-causing agents that multiply only in cells. Multiplication of DNA viruses is often lethal to the host cell, causing cell lyses and concomitant release of new virus particles. Many clinical manifestations of viral infection reflect these cytolytic properties. RNA viral infection, on the other hand, generally leads to the nonlethal release of progeny viral products. DNA and RNA viruses also have profound effects on the genetic makeup of a host cell and can lead to the production of tumors and diseases such as viral encephalitis.
For many viral diseases, efficient drugs do not exist which specifically act on the vital life cycle. The majority of viral replication machinery is of host origin and, therefore, inhibition of the viral processes would also result in inhibition of host function. There are a limited number of drugs which have attempted to exploit subtle differences between viral and host mechanisms. Included among these drugs are nucleotide analogs such as 5-iododeoxyuridine, arabinosyl cytosine and acyclovir.
Most viruses enter the cell by endocytosis at coated pits and can be found inside the cell in endosomes surrounded by lipid membranes of cell origin. Inside the cell the viral nucleic acids become free of the protective viral protein coat and are potential targets for the hydrolytic action of a nuclease.
Nucleases are the enzymes which hydrolyze phosphodiester bonds in unprotected DNA or RNA molecules. Cleavage of viral nucleic acids results in the destruction of the viruses genetic information and loss of infectivity. Pancreatic DNase has been shown to inhibit synthesis of viral DNA and reproduction inside cells infected with DNA-containing viruses such as vaccinia, herpes and adenoviruses. Likewise, pancreatic RNase has been demonstrated to be an efficient means of inhibiting synthesis of viral RNA and reproduction of tick-born encephalitis, poliomyelitis, foot-and-mouth disease and other RNA-containing viruses.
When they appear in the extracellular space, the nucleases are captured by the cells and are endocytosed through the same mechanism as viral particles. When viruses and nucleases are present in the extracellular space at the same time, they can subsequently be found inside the same cytoplasmic endosomes where they can act on the viral nucleic acid. Since nucleases inside endosomes are isolated from cellular components, host DNA or RNA is not susceptible to their action. Additionally, DNA and RNA, as a rule, are packaged within complicated structures forming complexes with proteins which provides additional defense against nucleases if, for example, there is a leakage of nucleases from the endosomes. At the same time, the vital nucleic acids are much less protected inside the cell during replication and transcription outside of the endosomes. Thus, the use of these enzymes as antiviral agents is safe and essentially devoid of any cell damaging properties.
DNase and RNase have previously been tested for treatment of vital disease. Neither shows any cytopathogenic, antimitotic or mutagenic effects when added to nutritive medium of cell cultures or administered parenterally to animals in high doses. Embryotoxic, teratogenic or other toxic effects are also not observed with these enzymes in animals. Clinical trials have demonstrated high therapeutic efficiency of DNase in treatment of herpes zoster, herpes simplex, herpetic keratitis, infectious mononucleosis, adenoviral conjunctivitis and nasopharyngitis caused by DNA-containing viruses, while RNase was shown to be efficient in treatment of viral encephalitis and meningitis caused by RNA-containing viruses. RNase does not appear to be effective in treating DNA viruses.
Despite successful treatments of well characterized viral infections under controlled conditions, more often than not, clinical observations of vital diseases do not allow the identification of the specific causal agent. Virological methods, on the other hand, do allow the identification of the causal agent but are generally time consuming, complicated and, in many cases, not available. Additionally, there are clinical cases where two or more DNA and RNA viruses act together causing the infectious disease. An example is bronchopneumonia in calves where the DNA virus, adenovirus, acts synergistically with the RNA virus, parainfluenza virus. Other RNA viruses also play a role during the course of infection in bronchopneumonia.
There thus exists a need for a method of simultaneously treating or preventing viral infections caused by a wide variety of DNA or RNA viruses which is safe and effective for use in humans, animals and plants. The present invention satisfies this need and provides related advantages as well.